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Who Makes It?
462
JOURNAL OF THE
AMERICAN PHARMACEUTICAL ASSOCIATION
acid was dissolved in 100 cc. of anhydrous methyl alcohol. To this was added an excess of diazomethane in anhydrous ether. The reaction mixture was allowed to stand at room temperature until no more diazomethane was present. The solvent was removed by distillation leaving a thick syrupy liquid. This was handled as in (a) and (b). (a) A portion of the syrupy liquid was treated directly with a n excess of methyl iodide. Upon standing a t room temperature overnight crystals formed in the reaction mixture. These were removed by filtration and recrystallized several times from methyl alcohol t o give white needles, m. p. 181-182'. The literature reports m. p. 167-168' (13) and 175-176" (7) for the methiodide of the dimethyl ester of N-methyl piperidine-2,6-dicarboxylic acid. And-Calcd. for CloHtsOaNCHJ: C, 37.0; H, 5.6. Found: C, 37.2; H, 5.6. (b) The remainder of the original syrupy liquid was allowed to stand in a desiccator for two months, at which time crystallization was apparent. Washing the partially crystallized mixture several times with acetone yielded an odorless white powder, m. p. 174-175'. This white powder was readily soluble in water. However, it resisted all attempts a t recrystallization and, therefore, was not submitted for analysis. T o obtain a crystalline derivative suitable for analysis the white powder was treated with an excess of methyl iodide. A crystalline methiodide, m. p. 180-181' was obtained. Mixed melting point determinations of these crystals with the original white powder and with the methiodide prepared directly from the original syrup showed it t o be identical with the latter. This was further confirmed by its analysis. From the analytical data on the methiodides as presented it would seem that the white powder is the dimethyl ester of scopolinic acid although it differs significantly in its properties from the compound reported by Willstatter and Lessing (13). Anal.-Calcd.for CloH1rOiN.CHsI: C, 37.0; H, 5.6. Found: C, 36.9; H, 5.7. Five grams of N-methyl-2,6-piperidine dicarboxylic acid was refluxed with 2 cc. of concentrated sulfuric acid in 100 cc. of anhydrous methyl alcohol for five hours. The methyl alcohol was distilled under reduced pressure and the residual liquid made neu-
tral with sodium carbonate. The neutralized mixture was then extracted with ether. The ether extractions were dried with anhydrous sodium sulfate. The ether was removed by distillation and a syrupy residue was obtained. When this syrupy residue was treated with an excess of methyl iodide a yellow crystalline deposit was obtained. This residue was recrystallized from methyl alcohol until a constant melting point of 151-152' was obtained. This melting point is in obvious disagreement with the melting point of the methiodide obtained from the esterifcation with diazomethane. The analysis is also in disagreement with that of the methiodide previously made. We are unable at this time to state the reason for the difference in melting points and analyses. Anal.-Calcd. for CloH~rO,N*CHaI: C, 37.0; H, 5.6. Found: C. 35.75; H. 5 5.
SUMMARY
Piperidine-2,6-dicarboxylicacid and its Nmethyl derivative have been prepared b y methods representing improvements on those formerly used. It is believed t h a t t h e N-methyl derivative is scopolinic acid (cis-N-methy1-2,6-piperidine dicarboxylic acid) on the basis of comparative melting points although the early literature is somewhat contradictory on this point. Further work to confirm this belief is being undertaken. REFERENCES
2072 (1902). (14) Heilkon 1 . "Dictionary of Organic Compounds
ed. 2, Oxford finiversity Press, New York, 1943, vol. p 1050. (15) Meyer. H., Monalsk., 24, 205(1903).
"
i,
WHO MAKES IT? The National Registry of Rare Chemicals, Armour Research Foundation, 33rd, Federal and Dearborn Streets, Chicago, Ill., seeks information on sources of supply for the following chemicals: Ammonium cyanide 7-Aminobutyric acid 3-Methylpentanol-3 Acetyl cyanide 5-Methylisoq$noline Acetyl phosphate Periltic acid scymnol Coniferyl alcohol Thioic acid
Mycolic acid Linamarin Myricin Phenolphthalein phosphate Biliverdin Perillyl alctehyde Cyanidin chloride Renin Hypertensinogen PhenamidIne
JOURNAL OF THE
AMERICAN PHARMACEUTICAL ASSOCIATION
acid was dissolved in 100 cc. of anhydrous methyl alcohol. To this was added an excess of diazomethane in anhydrous ether. The reaction mixture was allowed to stand at room temperature until no more diazomethane was present. The solvent was removed by distillation leaving a thick syrupy liquid. This was handled as in (a) and (b). (a) A portion of the syrupy liquid was treated directly with a n excess of methyl iodide. Upon standing a t room temperature overnight crystals formed in the reaction mixture. These were removed by filtration and recrystallized several times from methyl alcohol t o give white needles, m. p. 181-182'. The literature reports m. p. 167-168' (13) and 175-176" (7) for the methiodide of the dimethyl ester of N-methyl piperidine-2,6-dicarboxylic acid. And-Calcd. for CloHtsOaNCHJ: C, 37.0; H, 5.6. Found: C, 37.2; H, 5.6. (b) The remainder of the original syrupy liquid was allowed to stand in a desiccator for two months, at which time crystallization was apparent. Washing the partially crystallized mixture several times with acetone yielded an odorless white powder, m. p. 174-175'. This white powder was readily soluble in water. However, it resisted all attempts a t recrystallization and, therefore, was not submitted for analysis. T o obtain a crystalline derivative suitable for analysis the white powder was treated with an excess of methyl iodide. A crystalline methiodide, m. p. 180-181' was obtained. Mixed melting point determinations of these crystals with the original white powder and with the methiodide prepared directly from the original syrup showed it t o be identical with the latter. This was further confirmed by its analysis. From the analytical data on the methiodides as presented it would seem that the white powder is the dimethyl ester of scopolinic acid although it differs significantly in its properties from the compound reported by Willstatter and Lessing (13). Anal.-Calcd.for CloH1rOiN.CHsI: C, 37.0; H, 5.6. Found: C, 36.9; H, 5.7. Five grams of N-methyl-2,6-piperidine dicarboxylic acid was refluxed with 2 cc. of concentrated sulfuric acid in 100 cc. of anhydrous methyl alcohol for five hours. The methyl alcohol was distilled under reduced pressure and the residual liquid made neu-
tral with sodium carbonate. The neutralized mixture was then extracted with ether. The ether extractions were dried with anhydrous sodium sulfate. The ether was removed by distillation and a syrupy residue was obtained. When this syrupy residue was treated with an excess of methyl iodide a yellow crystalline deposit was obtained. This residue was recrystallized from methyl alcohol until a constant melting point of 151-152' was obtained. This melting point is in obvious disagreement with the melting point of the methiodide obtained from the esterifcation with diazomethane. The analysis is also in disagreement with that of the methiodide previously made. We are unable at this time to state the reason for the difference in melting points and analyses. Anal.-Calcd. for CloH~rO,N*CHaI: C, 37.0; H, 5.6. Found: C. 35.75; H. 5 5.
SUMMARY
Piperidine-2,6-dicarboxylicacid and its Nmethyl derivative have been prepared b y methods representing improvements on those formerly used. It is believed t h a t t h e N-methyl derivative is scopolinic acid (cis-N-methy1-2,6-piperidine dicarboxylic acid) on the basis of comparative melting points although the early literature is somewhat contradictory on this point. Further work to confirm this belief is being undertaken. REFERENCES
2072 (1902). (14) Heilkon 1 . "Dictionary of Organic Compounds
ed. 2, Oxford finiversity Press, New York, 1943, vol. p 1050. (15) Meyer. H., Monalsk., 24, 205(1903).
"
i,
WHO MAKES IT? The National Registry of Rare Chemicals, Armour Research Foundation, 33rd, Federal and Dearborn Streets, Chicago, Ill., seeks information on sources of supply for the following chemicals: Ammonium cyanide 7-Aminobutyric acid 3-Methylpentanol-3 Acetyl cyanide 5-Methylisoq$noline Acetyl phosphate Periltic acid scymnol Coniferyl alcohol Thioic acid
Mycolic acid Linamarin Myricin Phenolphthalein phosphate Biliverdin Perillyl alctehyde Cyanidin chloride Renin Hypertensinogen PhenamidIne